CONTACT INFORMATION

RESEARCH SUMMARY

Sirtuins as regulators of cardiac cellular growth, metabolism and longevity

My research interest is to understand pathophysiology of cardiovascular system, particularly growth and death of cardiomyocytes under various adverse conditions. There are many parallels between growth of cardiomyocytes and tumor cells, we therefore utilize both models to understand molecular basis of cellular growth. At the molecular level our focus is to understand how HDACs, particularly class-III HDACs (Sirtuins) regulate growth and death of cells under different pathophysiological conditions. Sirtuins are NAD-dependent deacetylases. They are implicated in regulation of myriad of biological functions, spanning from cell growth, metabolism to senescence. We are using human tissue as well as genetic, transgenic and surgical animal models to determine the signaling pathways contributing to pathologic cellular growth, and then to understand how sirtuins modify these pathways and protect cells from various insults.

We have demonstrated that two sirtuin isofroms SIRT3 and SIRT6 are endogenous negative regulators of cardiac growth, whereas another sirtuin analogue SIRT1 acts as a pro-growth molecule. Our studies have shown that sirtuin isoforms target PIP3/Akt signaling pathway to control cellular growth and survival. While SIRT1 deacetylates Akt to promote its binding to PIP3 and hence activation, SIRT3 controls ROS-mediated Akt activation and SIRT6 transcriptionally represses Akt at the level of chromatin. To take these studies from bench to bed-side we have screened a library of natural compounds and identified a phenolic compound as a specific activator of SIRT3. This molecule is capable of blocking tumor growth and cardiac hypertrophy both in pre- and post-treatment models. Since sirtuins are ubiquitous proteins, we believe that results obtained from studying their roles on growth and death of cardiomyocytes will have wide implications in understanding disease processes of many other tissues. We are extending these studies to define roles of sirtuins in regulation of TGF-β signaling and transformation of fibroblasts to myofibroblasts and induction of fibrosis in different tissues, particularly which is associated with aging.